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The Journal of Neuroscience, May 3, 2006, 26(18):4908-4916; doi:10.1523/JNEUROSCI.0476-06.2006

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Cellular/Molecular
Estrogen Receptors and Differentially Regulate the Transcriptional Activity of the Urocortin Gene

Paola Haeger,¹ María Estela Andrés,¹ María Inés Forray,^1,2 Claudia Daza,¹ Silvia Araneda,³ and Katia Gysling¹

¹Department of Cellular and Molecular Biology, Faculty of Biological Sciences and ²Department of Pharmacy, Faculty of Chemistry, Catholic University of Chile, 833-1010 Santiago, Chile, and ³Unité Mixte de Recherche Centre National de la Recherche Scientifique 5123, Universite Claude Bernard Lyon I, 69622 Villeurbanne Cedex, France

Correspondence should be addressed to Dr. Katia Gysling, Department of Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, 833-1010 Santiago, Chile. Email: kgysling{at}bio.puc.cl

Urocortin (Ucn), a highly conserved metazoan gene, is related to stress and feeding, behaviors with significant gender differences. We investigated whether estrogens regulate the expression of the Ucn gene using transient transfection in PC12 cells with the human Ucn (hUcn) promoter coupled to luciferase and either or estrogen receptors (ER or ER, respectively). The results demonstrate that estradiol (E₂) increases the activity of the hUcn promoter via ER, and decreases hUcn promoter activity through ER. Deletions of the hUcn promoter show that the increase in promoter activity mediated by E₂-ER depends on a promoter region containing a half-estrogen response element and an Sp1 site, and the decrease mediated by E₂-ER depends on a proximal promoter region containing a cAMP response element. Ucn and ERs coexist in neurons of rat hypothalamic nuclei, giving anatomical support for a direct effect of estrogen receptors on the Ucn gene. By in situ hybridization, we observed that cycling female rats have a higher number of cells expressing Ucn mRNA than males in the paraventricular nucleus of the hypothalamus (PVN) and the septum. Both of these brain nuclei are related to stress behaviors and express moderate levels of Ucn. Furthermore, Ucn mRNA was significantly decreased in the PVN and increased in the septum 30 d after ovariectomy. Acute E₂ administration to ovariectomized rats significantly increased Ucn mRNA expression in the PVN and septum. In conclusion, our in vitro and in vivo evidence suggests that estrogens exert a direct and differential transcriptional regulation of the Ucn gene.

Key words: estrogen; estradiol; stress; septum; gender differences; hypothalamus; CRH

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Received March 12, 2005; revised March 27, 2006; accepted March 28, 2006.

Correspondence should be addressed to Dr. Katia Gysling, Department of Cell and Molecular Biology, Faculty of Biological Sciences, Catholic University of Chile, 833-1010 Santiago, Chile. Email: kgysling{at}bio.puc.cl

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